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Investigating Class III fusion proteins as vaccine candidates against rabies virus and Epstein-Barr virus
No full textThe fusion proteins of enveloped viruses, responsible for membrane fusion and cell entry, are common targets for subunit vaccines. Fusion proteins undergo major conformational changes from a metastable pre-fusion state to a stable post-fusion one. The pre-fusion conformation may better expose neutralizing epitopes, and thus represent a better vaccine target, than the post-fusion. This phenomenon appears true for some Class I fusion proteins including those of respiratory syncytial virus and possibly SARS-CoV-2.
This thesis explores whether this principle applies to two Class III fusion proteins, where evidence remains limited. Rabies glycoprotein (RabG) and Epstein-Barr virus (EBV) glycoprotein B (gB) are investigated with a focus on understanding induction of neutralising antibody by their pre-fusion conformations.
For RabG, structure-guided mutagenesis strategies successfully stabilised the pre-fusion antigen and/or augmented expression in vitro. Promising mutations did not, however, improve the magnitude or quality of the antibody response raised to the wild-type form in mice.
For EBV gB, monoclonal antibodies (mAbs) were isolated from mice immunised with viral-vectored immunogens encoding the full-length antigen to express the membrane-stabilised, pre-fusion conformation of gB in vivo. 40 mAbs were successfully isolated against gB and investigated in detail, revealing previously-uncharacterised non-neutralising epitopes and a site of vulnerability on gB targeted by rare neutralising antibodies. Despite use of a screening method designed for discovery of conformationally specific anti-gB mAbs, none of those isolated displayed this phenotype.
Together, these findings do not support pre-fusion stabilisation for vaccines targeting two viruses employing Class III fusogens. Regarding RabG, however, the mutants characterised may still act as steps towards improving RabG immunogenicity in future vaccines. Similarly, whilst the mAbs isolated against EBV gB are not pre-fusion specific, they may represent useful tools for characterising gB as an antigen, including interrogation of whether non-neutralising antibodies can exert a protective effect in vivo.
Efforts to develop new vaccines targeting these proteins should not focus exclusively on pre-fusion stabilisation. Comparisons of vaccine platforms for antigen delivery, of protein candidates for subunit vaccines and on understanding the mechanisms by which antibodies to these fusion proteins convey protection remain critical for developing new rabies and EBV vaccines
Dissecting the neutralising antibody response to the porcine reproductive and respiratory syndrome virus to identify novel vaccine targets
Get PDFPorcine reproductive and respiratory syndrome viruses (PRRSV) continue to cause major economic losses to the global swine industry. The high degree of variability among circulating PRRSV strains, facilitated by an inherent propensity for rapid mutation, poses a significant challenge to the development of effective vaccines. Antibodies capable of broadly neutralising PRRSV strains are of great interest as tools to guide next-generation vaccine design. The conserved neutralising epitopes on PRRSV glycoproteins, however, remain unknown, and our understanding of the mechanisms behind antibody-mediated neutralisation of PRRSV is incomplete. To address this, recombinant soluble forms of the PRRSV-1 minor envelope complex glycoproteins, GP2, GP3, and GP4, were produced using a mammalian cell expression system. Serum from hyperimmunised pigs were screened for binding to these proteins and GP3 was identified as the most highly recognised by antibodies in these sera. Fluorescently tagged GP3-tetramers were therefore constructed and used to isolate single B cells from a hyperimmune pig by flow cytometry. mRNA encoding immunoglobulin VH and VL regions was amplified using a semi-nested RT-PCR workflow, sequenced, and complementarity-determining regions annotated using the IgMAT tool. Fifteen unique heavy and light chain pairs were cloned and expressed as recombinant monoclonal antibodies (mAbs). mAbs were evaluated for their specificity, cross-reactivity and neutralising potency by ELISA, immunostaining of PRRSV-infected cells, and virus-neutralisation tests. The binding epitope of selected anti-GP3 mAbs was mapped to a conserved sequence but did not show neutralising activity in vitro. It is speculated that the binding site may represent a decoy epitope. A pilot study investigating the immunogenicity of GP3 further demonstrated a lack of a neutralising antibody response despite high titres of GP3-binding antibodies. A workflow has been established for the isolation of porcine mAbs that could be used in future work to further dissect the immune response to PRRSV infection and vaccination
Advancing global healthcare leadership: enhancing evidence-based practice competencies in postgraduate programmes for non-clinical executives
Get PDFGlobal healthcare systems necessitate an innovative approach to leadership, particularly for non-clinical executives, to address growing complexities worldwide. Evidence-based practice combines the best known research with clinical expertise and patient values. There is a need to add evidence-based practice to postgraduate programme curricula to train healthcare leaders in best practices for decision-making, especially non-clinical executives.
This dissertation explores university postgraduate global healthcare leadership programme websites to learn the extent to which evidence-based practice competencies are incorporated into the programmes. A textual content analysis was conducted in review of 114 programmes at 108 universities. The findings reveal a noteworthy gap in the engagement of evidence-based competencies in non-clinical executive leader training.
As a result, the study advocates for the recognition of Global Healthcare Leadership as an academic discipline or field of study. Global Healthcare Leadership is an interdisciplinary model in which Global Healthcare, Global Leadership, and Evidence-Based Practice collectively form the eld of Global Healthcare Leadership. The dissertation concludes that an integrated, interdisciplinary approach is crucial for preparing non-clinical executives to address the multifaceted challenges of global healthcare.
The growing recognition of global healthcare leadership as a distinct academic discipline has driven the integration of global healthcare and global leadership competencies into postgraduate programmes. There is a rising emphasis on incorporating evidence-based practice to cultivate scholar-practitioners. The dissertation urges that the academic discipline train scholar-practitioners ready for leading in the global healthcare milieu
No stock, high stakes problems: perspectives on the ethics of whether to source medical products of uncertain quality for humanitarian health projects during urgent stock-outs
No full textSubstandard and falsified medical products threaten patient lives and, although a global problem, disproportionately affect low- and middle-income countries. International Non-Governmental Organisations (iNGOs) delivering humanitarian health services in these regions often import medical products from trusted international sources. However, if extended health supply chains fail or demands suddenly change, iNGOs face a tragic choice: urgently source medical products of uncertain quality or suspend healthcare provision until resupplied. I term this situation a ‘no stock, high stakes’ problem. This ethical problem is previously undocumented; existing literature focuses on the quality or availability of medical products, failing to attend to the tension between them.
A range of qualitative research methods were employed to obtain a thick description of this difficult decision from the perspectives of those who have experienced it. I conducted a stakeholder analysis and used purposeful, stratified sampling methods to identify suitable participants. Vignettes constructed from interview-generated data were used as both an elicitation technique and to convey complex findings in the thesis. Reflexive thematic analysis was used to interpret the dataset, informed by discourse analysis techniques to uncover the implicit significance of participants' key phrases and behaviours.
Findings indicate that participants commonly experience ‘no stock, high stakes’ problems as moral problems, and that they are intensified by the conflicting expectations of the donor and Host Government. A dominant neoliberal paradigm incentivises iNGOs to preference the donor’s expectations, leading them to undermine the authority of the State and prioritize fiscal responsibility (via compliance with Quality Assurance policies) over patient care. Participants responsible for implementing donor policies tended to prioritize quality (and economic stability) to a greater extent than those in proximity to patients, who often prioritised continued healthcare provision over personal or organisational risk. These inconsistencies highlight a health injustice in patient care necessitating urgent normative guidance and policy review
Is “nature” a policy solution to mental health in schools?
Get PDFThe UK faces a growing youth mental health crisis (NHS, 2023; RCPsych 2025). Schools may play a key role in preventing these difficulties from worsening.
The integration of nature-based programs (NbPs) into school settings has been proposed as a policy solution to address such mental health challenges but robust evidence is lacking (Lomax et al., 2024), particularly at the secondary school level.
This Sprint utilised an implementation science framework to co-produce evidence on NbPs in secondary schools with stakeholders including policymakers from the Government’s Department for Education (DfE), young people, and educators.
Using a range of methodologies we are evaluating effectiveness, amplifying stakeholder voices, and creating actionable, evidence-based education policy insights
Assessing the limits on size-pitch mapping reveals the interplay between top-down and bottom-up influences on relative crossmodal correspondences
Get PDFCertain sensory dimensions, such as visual size and auditory pitch, are consistently associated, resulting in performance facilitation or inhibition. The mechanisms underlying these crossmodal correspondences are still the subject of debate: The relative or absolute nature of crossmodal mappings is connected to this debate, as an absolute mapping points to a bottom-up process, whereas a relative one is evidence of stronger top-down influences. Three experiments were conducted (including overall N = 207 participants), based on two different tasks, designed to explore a wide range of size-pitch crossmodal mappings. In Experiment 1, the participants were instructed to freely manipulate stimuli varing along a given dimension to ‘match’ the other. The results revealed evidence for a quasi-absolute mapping, but the correspondences shifted depending on the participants’ auditory or visual attentional focus. In Experiment 2, the participants performed a visual speeded categorization task, involving a wide range of auditory task-irrelevant pitches, including the “preferred” ones, estimated on the basis of the results of Experiment 1. The results revealed a rather relative mapping, corroborating a top-down influence on the correspondence effect. Experiment 3 was designed to determine whether the relative mapping involved has boundary. The results confirmed that the larger the interval between pitches (i.e., more perceptually salient), the stronger the congruence effect, thus highlighting bottom-up facilitation. Taken together, these findings reveal that the size-pitch correspondences are sensitive to task-related top-down factors, as well as to stimulus-related bottom-up influences, ultimately revealing the adaptive nature of this kind of multisensory integration
Frontier AI regulation: what form should it take?
Get PDFFrontier AI systems, including large-scale machine learning models and autonomous decision-making technologies, are deployed across critical sectors such as finance, healthcare, and national security. These present new cyber-risks, including adversarial exploitation, data integrity threats, and legal ambiguities in accountability. The absence of a unified regulatory framework has led to inconsistencies in oversight, creating vulnerabilities that can be exploited at scale. By integrating perspectives from cybersecurity, legal studies, and computational risk assessment, this research evaluates regulatory strategies for addressing AI-specific threats, such as model inversion attacks, data poisoning, and adversarial manipulations that undermine system reliability. The methodology involves a comparative analysis of domestic and international AI policies, assessing their effectiveness in managing emerging threats. Additionally, the study explores the role of cryptographic techniques, such as homomorphic encryption and zero-knowledge proofs, in enhancing compliance, protecting sensitive data, and ensuring algorithmic accountability. Findings indicate that current regulatory efforts are fragmented and reactive, lacking the necessary provisions to address the evolving risks associated with frontier AI. The study advocates for a structured regulatory framework that integrates security-first governance models, proactive compliance mechanisms, and coordinated global oversight to mitigate AI-driven threats. The investigation considers that we do not live in a world where most countries seem to be wishing to follow European Union ideals, and in the wake of this particular trend, this research presents a regulatory blueprint that balances technological advancement with decentralised security enforcement
A genre, scoring and authorship analysis of AI-generated and human-written business refusal emails: is there still a case for business writing training?
Get PDFIn a business context, writing negative messages such as refusals to requests is particularly challenging, as the act of refusal can damage the relationship between writer and reader. Generative artificial intelligence (AI) tools have shown the capacity to assist with various writing tasks, but do these tools remove the need for business writing training? This study analysed the genre moves and steps that typify business refusal texts generated by ChatGPT (n = 18) and Gemini (n = 18) alongside human-written texts (n = 18). To assess writing quality, experienced business communication instructors (N = 36) scored the texts on an established rubric for evaluating business written professional communication. Assessors also made authorship judgements as to whether each text was AI-generated or human-written and provided rationales for their decisions. The views of the instructors regarding the use of AI tools for writing in the workplace were also captured.
The genre analysis showed that AI-generated texts were formulaic and largely followed the same moves and steps, regardless of text type or audience, whereas human-written texts were more nuanced and flexible in their adoption of genre conventions. On writing quality, human-written texts achieved the highest mean scores, followed by Gemini texts and finally ChatGPT. Inferential statistics revealed that Gemini texts did not differ significantly in the rubric evaluation scores compared to human-written texts, although Chat-GPT produced texts received significantly lower evaluations of writing quality. Participants were able to identify authorship of AI-generated texts with an accuracy rate of 68.1%, and human-written texts were correctly identified 86% of the time. Qualitative data revealed that assessors were most concerned with three broad characteristics of the texts: tone, relationship and formality; language choice and grammatical accuracy; content, detail and structure. Insights into key differences between AI-generated texts and human writing drawn from these results are used to inform five key areas of focus for teaching business writing in the AI age
Reassessing the HMS Challenger collection as a late 19 th century surface ocean indicator using X-ray micro-computed tomography
Get PDFPlankton tow net samples collected during the HMS Challenger expedition (1872–1876) have highlighted the potential to provide an unique window into past oceanic conditions. This study aims to assess the suitability of HMS Challenger sediment samples as indicators of late 19th century surface oceanic conditions using X-ray micro-computed tomography (μCT). We used μCT to examine all 21 available Challenger samples from the global ocean that were labelled as ‘tow-net at dredge’, ‘weights’, or ‘trawl’. Our analysis reveals that most samples contain benthic foraminifera shells, along with high concentrations of foraminiferal fragments and detrital quartz grains, while the remaining samples consist of sedimentary material devoid of calcareous microfossils. These findings suggest that these tow-net samples include resuspended bottom sediments rather than exclusively surface-derived material. This distinction is critical because it demonstrates that two types of Challenger tow-net samples exist: surface ocean samples and deep-water tow-net samples that incorporate seafloor material. The surface tow-net samples were recently located and are referenced in this study. These findings highlight the importance of re-evaluating historical sediment collections with modern analytical techniques to ensure accurate paleoceanographic interpretations. Furthermore, the study demonstrates the effectiveness of μCT as a non-destructive tool for sediment analysis, allowing for the detailed examination of collections without the need for washing or wet sieving
Functional Graphene Fiber Materials for Advanced Wearable Applications
Get PDFGraphene fiber materials have emerged as key enablers in the advancement of wearable electronics due to their outstanding electrical conductivity, mechanical strength and flexibility. This review explores the fabrication techniques of graphene fibers, including wet spinning, electrospinning and dry spinning, which have been refined to produce high-performance fibers tailored for various wearable applications. Graphene fibers demonstrate exceptional functionality in wearable sensing technologies, such as strain, pressure and humidity sensors, while also showing promises in flexible energy storage devices like supercapacitors and batteries. Moreover, fabrication techniques like weaving, spinning and additional encapsulations have enabled the integration of graphene fibers into smart textiles, enhancing flexibility and durability. These methods ensure seamless electronic integration into fabrics for applications in flexible displays and wearable systems. By summarizing all the advances of graphene fibers in wearable electronics, this review provides a roadmap for future research directions. Future developments will focus on enhancing structural performance, hybridization with other materials and scalable fabrication techniques to support commercialization. These advancements position graphene fibers as a critical material for next-generation wearable electronics, offering seamless integration of functionality, comfort and durability. Graphical Abstract